Mirabegron is chemically known as 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide (I).
Mirabegron is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Mirabegron is marketed under the trade name Myrbetriq®.
U.S. Pat. No. 6,346,532 discloses Mirabegron or its salt thereof and process for its preparation.
U.S. Pat. No. 7,342,117 discloses polymorphic forms of Mirabegron namely α-Form crystals and β-Form crystals of Mirabegron.
According to the US '117 patent, α-Form crystals of Mirabegron (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 degrees and further characterized by differential scanning calorimetry exhibiting a single endotherm with a peak temperature of about 142 to 146° C.) can be prepared by adding of β-Form crystals of Mirabegron with water and alcohol and heating at about 80° C. and cooling the solution. The resulting solution was seeded to provide the α-Form crystals of Mirabegron.
According to the US '117 patent, β-Form crystals of Mirabegron (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 9.68, 19.76, 20.72, 22.10 and 23.52 degrees and further characterized by differential scanning calorimetry exhibiting two broad endotherms with peak temperature of about 90° C. to 110° C. and 142 to 146° C.) can be prepared by reacting aminophenyl aminophenethanol hydrochloride (II) with 2-amino-4-thiazoleacetic acid (III) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) and further treated with sodium hydroxide in DM water to produce wet cake of β-Form crystal of Mirabegron. This wet β-Form crystal of Mirabegron is treated with water and alcohol and the resulting solution was cooled and filtered to dryness.
The process is as shown in Scheme-I below:

US 2014/0206729 A1 discloses a process for the preparation of α-Form crystals of Mirabegron by dissolving Mirabegron in a solvent selected from methanol, ethanol, tetrahydrofuran, ethyl acetate, toluene or mixtures thereof to provide a solution, cooled the solution and isolated Mirabegron α-Form crystals.
US '729 also discloses variant process for the preparation of α-Form crystals of Mirabegron by dissolving Mirabegron in a mixture of methanol and water to provide a solution, cooled the solution and isolated α-Form crystal of Mirabegron.
US '729 also discloses variant process for the preparation of α-Form crystals of Mirabegron by providing a solution of Mirabegron in a solvent selected from tetrahydrofuran, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, methyl isobutyl ketone, chlorobenzene or mixtures thereof; combining the solution with an anti-solvent selected from cyclohexane, methylcyclohexane, n-heptane, diisopropyl ether, methyl tertiary butyl ether, toluene, water, provided that when methanol was used as a solvent then anti-solvent was other than water; and isolated α-Form crystal of Mirabegron.
WO 2015/044965 A 1 discloses a process for the preparation of α-Form crystals of Mirabegron by adding first solvent to the reaction mass of Mirabegron and then basifying the solution and optionally heated the reaction mixture. Separated the organic layer and washed with water and separated organic layer followed by adding second solvent to obtain α-Form crystals of Mirabegron.
α-Form crystals of Mirabegron prepared by above prior art process contain polymeric impurities or by-products originating from production processes or storage, which gives α-Form crystals of Mirabegron with low purity and assay. Pure α-Form crystals of Mirabegron preparation involves repeated crystallization and loss of yield.
The present invention is directed to a new, efficient and eco friendly process for the preparation of α-Form crystals of Mirabegron in pure form without any organic solvent. The present inventors attempted various crystallization methods without using any organic solvents at several temperatures with a certain amount of Mirabegron.
The present inventors worked on crystallization techniques and found that dilution, and temperature plays an important role in obtaining α-Form crystals of Mirabegron in pure form.
α-Form crystals of Mirabegron of present invention is having good stability and purity in different conditions and can also be prepared by an efficient, economic and reproducible process particularly in large scale preparation with free flowing nature.